Cyclocondensation of 2-Fluoro-5-nitrobenzaldehyde with Amidines. New Synthesis of Isoquinolines

The direction of the cyclocondensation of 2-fluoro-5-nitrobenzaldehyde with five amidines having -hydrogen atoms has been studied. It was established that depending on the structure of the amidine the main products of the reaction may be not only quinazolines but also 3-aminoisoquinolines. A new convenient route has been found for the synthesis of 3-aminoisoquinolines consisting of the cyclocondensation of -acylacetamidines with 2-fluoro-5-nitrobenzaldehyde.     

Montmorillonite K10-catalyzed synthesis of N-fused imino-1,2,4-thiadiazolo isoquinoline derivatives

A novel synthesis of N-fused imino-1,2,4-thiadiazolo derivatives is described. This approach involves the inexpensive, nontoxic, recoverable, and easy to handle montmorillonite K10 that catalyzes the coupling of 3-aminoisoquinolines and phenylisothiocyanates to afford the N-fused imino-1,2,4-thiadiazolo isoquinoline motifs in exemplary yields. The main attractions of this synthetic strategy were simple procedure and excellent yields.     

A new synthesis of 4-oxygenated β-carboline derivatives by Fischer indolization

A new and short synthetic route to the 4-methoxy-β-carboline skeleton is described. The route involves Fischer indolization of enehydrazine of 1-tosylpiperidine-3,5-dione and successive acetalization-elimination for aromatization of 1,2,3,4-tetrahydro-2-tosyl-9H-β-carbolin-4-one. This method is efficiently applicable to synthesis of the benzene-part substituted 4-oxygenated β-carboline derivatives.     

Synthesis of 1-aminoisoquinolines via Rh(III)-catalyzed oxidative coupling

[RhCp*Cl(2)](2) can catalyze the oxidative coupling of N-aryl and N-alkyl benzamidines with alkynes to give N-substituted 1-aminoisoquinolines in high selectivity.     

An efficient route to 1-aminoisoquinolines via AgOTf-catalyzed reaction of 2-alkynylbenzaldoxime with amine

2-Alkynylbenzaldoxime reacts with amine catalyzed by silver triflate under mild conditions, leading to 1-aminoisoquinolines in good yield. This reaction proceeds efficiently with good functional group tolerance.     

An expeditious approach to 1-aminoisoquinolines via an unexpected reaction of 2-alkynylbenzaldoxime, carbodiimide, with bromine

A three-component reaction of 2-alkynylbenzaldoxime, carbodiimide, and bromine provides a novel and efficient approach to functionalized 1-aminoisoquinolines. This unexpected reaction proceeds through electrophilic cyclization, [3+2] cycloaddition, rearrangement and hydrolyzation.     

Diastereoselective α-iminoamine rearrangement: asymmetric synthesis of (R)-(−)- and (S)-(+)-2-benzyl-2-hydroxycyclohexanone

A convenient asymmetric synthesis of both (R)-(−)- and (S)-(+)-2-benzyl-2-hydroxycyclohexanones starting from racemic 2-benzyloxycyclohexanone and the chiral auxiliary 1-phenylethylamine is reported. The route involves a [1,3]-sigmatropic shift and a new diastereoselective α-iminoamine rearrangement of a 2-benzyl-2-iminocyclohexanamine substrate.     

Synthesis of 2-amino-3-hydroxy-4-substituted pyridines via regioselective metalation of 3-(1-ethylpropyl)-[1,3]oxazolo[4,5-b]pyridin-2(3H)-one and application to corticotropin releasing factor1 receptor ligands

An efficient route to the preparation of 2-amino-3-hydroxy-4-substituted pyridines is described. The key step involves the regioselective metalation and subsequent alkylation of the [1,3]oxazolo[4,5-b]pyridin-2(3H)-one ring system. Base hydrolysis provides access to a variety of 4-substituted pyridines. This chemistry is proved to be useful for the synthesis of corticotropin releasing factor₁ receptor ligands.     

A process for the preparation of 1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole

A synthesis of 1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1-hi]indole is described exemplifying a new synthetic route to medicinally interesting compounds. The key step involves a cyclization of 2-(2,3,3a,8b-tetrahydrocyclopenta[b]indol-4(1H)-yl)-ethanamine with aqueous formaldehyde in the presence of trifluoroacetic acid.     

A direct arylation-oxidation route to 3-arylisoindolinone inhibitors of MDM2-p53 interaction

A route to the MDM2-p53 inhibitor isoindolinone pharmacophore from a pre-formed phthalimide is detailed. The route involves treatment of 3-hydroxy-2-(n-propyl)isoindolinone with a substituted benzene in the presence of triflic acid. The resulting 3-aryl-2-(n-propyl)isoindolinones are then oxidized to the corresponding 3-hydroxy-3-aryl-2-(n-propyl) isoindolinones by treatment with 2,2’-bipyridinium chlorochromate. The benzylic oxidation represents a rather rare oxochromium (VI)-mediated reaction in which a selective C-H to C-OH transformation occurs.     

An efficient synthesis of 6H,7H-chromeno[4,3-b]chromenes and 6,7-dihydrothio chromeno[3,2-c]chromenes as 9-substituted xanthene like analogs

An efficient synthetic route with good overall yields to access 7-aryl/heteroaryl/alkyl substituted 6H,7H-chromeno[4,3-b]chromene, and 6,7-dihydrothiochromeno[3,2-c]chromene scaffolds has been developed. The route to these xanthene-like analogs involves a three-step reaction sequence: (1) Michael addition of readily available phenol and thiophenol to 4-chloro-2,2-dimethyl-2H-chromene-3-carbaldehyde, (2) Grignard reaction of different aryl, heteroaryl and alkyl magnesium bromides on the resulting carbaldehydes followed by (3) FeCl₃ catalyzed spontaneous intramolecular Friedel-Craft’s reaction on the diarylmethyl carbinols.     

Synthesis of 2-substituted piperazines via direct α-lithiation

A novel efficient synthetic route towards the pharmaceutically relevant 2-substituted piperazine class is described. The key step involves α-lithiation of N-Boc piperazines, followed by reaction with several electrophiles. To obtain high yields, in some cases transmetallation to copper after the lithiation step is required.     

One-pot synthesis of functionalized furamide derivatives via a three-component reaction between an amine, diketene and dibenzoylacetylene in the presence of triphenylphosphine

An effective route to functionalized furamide derivatives is described. This involves reaction of N-alkyl-3-oxobutanamides, derived from the addition of amines to the diketene, and dibenzoylacetylene in the presence of triphenylphosphoine. The reactive 1:1 intermediate obtained from the addition of triphenylphosphine to dibenzoylacetylene was trapped by OH-acids such as N-alkyl-3-oxobutanamide to produce functionalized furamide derivatives.     

Synthetic entry to 8-(o-nitrophenyl-2-azabicyclo[3.3.1]nonan-7-ones. Intermediates for the synthesis of strychnos-type systems.

The first synthetic route to 8-aryl-2-azabicyclo-[3.3.1]nonan-7-ones (e.g. 5) is reported. The synthesis involves acid cyclization of an appropriate 4-acetonyl-2-piperidinecarbonitrile (4) which, in turn, is obtained from the corresponding piperidine (3) by a modified Polonovski reaction. The o-nitrophenyl substituent of 3 is introduced by arylation of 4-piperidineacetoacetate 1 with o-fluoronitrobenzene followed by acid hydrolysis. The conversion of α-(o-nitrophenyl)ketone 5 to the bridged azocinoindole 7, an intermediate in the synthesis of deethyltubifolidine, is also reported.     

One-pot synthesis of 4,5-dihydro-1H-pyrrol-3-carboxamide derivatives via a four-component reaction

An effective route to functionalized 4,5-dihydro-1H-pyrrol-3-carboxamide derivatives is described. This involves reaction of N-alkyl-3-oxobutanamides, which result from the addition of an amine to the diketene, and a primary amine in the presence of dibenzoylacetylene. The 1,3-dicarbonyl compounds obtained from the addition of an amine to diketene were trapped with a primary amine to produce (Z)-3-(alkylamino)-N¹-alkyl-2-butenamide, which reacts with dibenzoylacetylene to produce 4,5-dihydro-1H-pyrrol-3-carboxamide derivatives.     

Non-phosgene route to unsymmetrical ureas from N-Cbz-α-amino acid amides

A convenient method toward the synthesis of α-amino acid-derived unsymmetrical ureas 2 is described herein. This route involves an interesting rearrangement of amides of N-Cbz-α-amino acids 1, which presumably entails the intermediacy of hydantoins that is followed by hydrolysis to afford unsymmetrical ureas 2 in quantitative yields and high purity.     

A simple and facile route for the synthesis of 2H-1,4-benzoxazin-3-(4H)-ones via reductive cyclization of 2-(2-nitrophenoxy)acetonitrile adducts in the presence of Fe/acetic acid

A simple route for the synthesis of 1,4-benzoxazin-3-(4H)-ones is described herein. This method involves the reductive cyclization of 2-(2-nitrophenoxy)acetonitrile adducts in the presence of Fe/acetic acid in good to excellent yields. This system was compatible with various other functional groups.     

A novel chemo-multienzymatic synthesis of bioactive cyclophellitol and epi-cyclophellitol in both enantiopure forms

A new route to synthesize cyclophellitol and epi-cyclophellitol from racemic starting materials in enantiopure forms has been developed. The synthesis involves a multi-enzymatic biotransformation pathway of the novel cyano-cyclitol (1R,4S,5R,6R)/(1S,4R,5S,6S)-4,5,6-trihydroxycyclohex-2-enecarbonitrile by a cooperative use of lipase, nitrile hydratase, and amidase.     

Synthetic studies directed toward guianolides: an organoiron route to the 5,7,5 tricyclic ring system

A diastereoselective route to the 5,7,5-tricyclic core of the guianolides is presented. This route relies on Cope rearrangement of a divinylcyclopropane prepared by alkenyl Grignard addition to a (pentadienyl)iron(+1) cation, followed by oxidative decomplexation. An additional key reaction involves oxidative rearrangement of a 3,4-epoxy-1,7-diol to generate a γ-lactone. The relative stereochemistry of this product was established by X-ray crystallography.     

Development of a scalable synthetic route towards a 2,2,6-trisubstituted chiral morpholine via stereoselective hydroalkoxylation

A scalable synthetic route towards a chiral 2,2,6-trisubstituted chiral morpholine, which is a known opioid antagonist, was developed. The synthetic route involves incorporating an aryl group via Suzuki-Miyaura coupling and stereoselective hydroalkoxylation catalyzed by trifluoromethanesulfonic acid. Late stage incorporation of both the aryl and N-alkyl groups make this route suitable for further SAR studies on this molecule.